Several decades of research continue to show that activity-dependent changes in synaptic efficacy are critical to experience-dependent modification of neural function. The mechanisms underlying these changes are more diverse than previously expected. Recently, a new type of use-dependent synaptic plasticity that requires retrograde signaling by endogenous cannabinoids (endocannabinoids) has been identified in several brain structures. Endocannabinoids are produced on-demand from neurons, cross the synaptic cleft, and by activating presynaptic cannabinoid receptors, suppress transmitter release in a transient or long-term manner. The mechanisms and physiological consequences of endocannabinoid-mediated synaptic plasticity are not fully understood. The experiments proposed here are designed to investigate the molecular mechanisms downstream of cannabinoid receptor activation, induction rules under more physiological conditions, and functional impact of eCB-mediated synaptic plasticity. To address these issues, we will focus on the hippocampus in vitro where we have found that endocannabinoids mediate long-term depression at inhibitory synapses. We will also extend our studies of eCB-plasticity to the dentate gyrus and prefrontal cortex, two brain areas where eCBs are thought to play a role in the etiology of epilepsy and schizophrenia, respectively. By modulating synaptic transmission, endocannabinoids participate in a wide range of brain function including cognition, motor control, aversive and feeding behaviors, pain perception and reward. Dysregulation of endocannabinoid signaling has been implicated in several neurological and psychiatric conditions. A better understanding of endocannabinoid-mediated plasticity is crucial not only a more realistic representation of neural function but also to identify how marijuana abuse may affect the brain, and ultimately, to develop novel therapeutic strategies targeting the endocannabinoid system. PUBLIC HEALTH RELEVANCE: Endocannabinoids have emerged as key regulators of basic neural functions by mediating activity-dependent synaptic plasticity. Drugs that target these molecules and their receptors could be extremely useful for the development of new treatments for a variety of neurological and psychiatric disorders. Research on the endocannabinoid system not only helps in gaining a greater understanding of how marijuana acts in the brain and why it is abused, but it also provides new clues about how the brain works.